Immune Dysregulation, Inflammation in Characterizing Women with Vulvodynia, Depression, and Both

Abstract

Background:

Depression and vulvodynia are often comorbid. The onset of depression and vulvodynia may be immune and/or stress/environmentally induced. We explored whether vulvodynia, depression, or both occur in response to a Th1-mediated versus Th2-mediated immune response.

Materials and Methods:

We analyzed data from a case–control study of clinically confirmed vulvodynia and history of depression determined through structured clinical interviews. Immune dysregulation and inflammation were categorized based on the following self-reported conditions: rheumatoid arthritis, Sjogren's disease, scleroderma, systemic lupus erythematosus, inflammatory bowel disease, fibromyalgia, osteoarthritis, polycystic ovarian syndrome, diabetes mellitus, uterine fibroids, asthma, atopic dermatitis, and allergic rhinitis. Logistic regression analyses were adjusted for marital status, body mass index, age, and pack years.

Results:

Women with systemic immune dysregulation had higher odds of depression (adjusted odds ratio [aOR] = 1.61, confidence interval [95% CI]: 0.65–3.98), vulvodynia (aOR = 2.45, 95% CI: 1.00–5.96), and comorbid depression and vulvodynia (aOR = 4.93, 95% CI: 2.19–11.10) versus neither condition. Women reporting local immune dysregulation had similar odds of depression (aOR = 1.89, 95% CI: 0.99–3.59), vulvodynia (aOR = 2.12, 95% CI: 1.08–4.18), and comorbid depression and vulvodynia (aOR = 1.96, 95% CI: 0.98–3.90). Women with Th2 inflammation had similar odds of depression (aOR = 2.23, 95% CI: 1.05–4.77) and vulvodynia (aOR = 2.56, 95% CI: 1.20–5.49). Women with Th1 or Th2 inflammation had similar odds of comorbid depression and vulvodynia (aOR = 3.03, 95% CI: 1.48–6.19; aOR = 3.14, 95% CI: 1.49–6.60, respectively).

Conclusions:

Our results suggest that an imbalance of cytokines, indicated by the presence of one or more immune-related health conditions, is associated with an increased risk of vulvodynia and/or depression.

Introduction

Vulvodynia is defined as unexplained chronic vulvar discomfort with no consistent clinically visible pathology.¹ A key symptom of vulvodynia is experiencing vulvar burning or pain on contact,¹ and this disorder has been shown to impact 8% of women by the age of 40 years.²

Scientific evidence suggests that vulvodynia may develop as a consequence of an altered immune-inflammatory response to chronic infections, inflammation due to other immune-related conditions, or other allergenic exposures.^3–6 Interestingly, we and others have shown strong associations between exposures that elicit a stress immune response, such as childhood victimization, depression, anxiety, and rumination, and the risk of developing vulvodynia later in life.^7–10 Similar to vulvodynia, the literature looking at the pathophysiology of depression indicates that an imbalance of the immune system leads to an increased risk of depression.^11–15 Thus, we believe that both stress immune and environmentally induced hyperimmune responses may be antecedent to the onset of vulvodynia and depression.

Immune regulation involves the balance between the different types of immune responses.¹⁶ A balance between T-helper 1 (Th1) and T-helper 2 (Th2) activity, distinguished by the type of cytokines produced by the T-helper cell subsets, is key for the body to maintain homeostasis.^16,17 It is thought that an imbalance between Th1 and Th2 immunity leads to pathological states such as autoimmunity driven by a stronger Th1 response, or atopy driven by a stronger Th2 response.^18,19 Cytokine dysregulation has also been clearly implicated in the pathogenesis of depression.^14,20–23 What is less clear, however, is whether vulvodynia, depression, or both are more likely to occur in response to a Th1-driven versus Th2-driven immune response.

Few studies have directly compared the potential impact of Th1 cytokines or Th2 cytokines on the risk of vulvodynia and/or depression within the same population. Therefore, we sought to assess this association utilizing data from a case–control study of clinically confirmed vulvodynia where history of depression was also obtained using structured clinical interviews for DSM-IV.

Methods

Data and study population

The University of Minnesota and Boston University Institutional Review Boards approved this study, and all participants provided written consent. Further details of the study have been previously reported.²⁴ In brief, 30,676 women 18–40 years of age were identified from the administrative database of a large health care network in the Minneapolis/Saint Paul metropolitan area between March 2010 and October 2013. Each woman was screened for a history of vulvar pain symptoms, regardless of their reason for an outpatient clinic visit.

Self-administered questionnaires were used to assess lifetime history of vulvar pain symptoms. After reviewing the questionnaire, clinical visits were conducted for women likely to meet the International Society for the Study of Vulvovaginal Disease (ISSVD) criteria for vulvodynia.¹ Among the 350 subjects clinically examined, 234 women were clinically confirmed and enrolled as cases.

Women from the same pool of screened participants with no history of vulvar discomfort were randomly selected to serve as controls. Among the 251 women selected and consented to participate, 234 were clinically confirmed as having no vulvar pain and were enrolled. Enrolled controls were matched to cases and assigned a “reference age” corresponding to the case's age at first onset of vulvar pain. Controls were required to be older than the age at which their case was diagnosed with vulvodynia.

The interval between actual age and age at onset of vulvodynia in cases, and that between actual age and reference age in controls, was no more than 2 years. For cases, we attempted to collect all historical information within the temporal context that preceded their age at first onset of vulvar pain. The same temporal context was used for collecting data among controls based on their assigned reference age. Thus, exposures were assessed using the same temporal context for both cases and controls.

Exposure classification

Medical history interviews were self-administered to cases and controls. Based on medical history responses, participants were first categorized as having or not having any of the following conditions before the onset of vulvar pain or reference age among controls: rheumatoid arthritis, Sjogren's disease, scleroderma, systemic lupus erythematosus, inflammatory bowel disease, fibromyalgia, osteoarthritis, polycystic ovarian syndrome, diabetes mellitus, uterine fibroids, asthma (based on medication use), atopic dermatitis, and/or allergic rhinitis.

We then categorized these conditions into mutually exclusive immune dysregulation categories of Th1 and Th2 dysregulation. Disease states were categorized as predominant Th1 or predominant Th2 as well as having systemic (high) cytokine levels or localized (low) cytokines levels based on literature review and the predominant cytokine associated with each disease state.^25–47 Table 1 provides a breakdown of the categorization of disease by immune dysregulation and inflammation type.

Table 1.

Categorization of Disease by Immune Dysregulation Type and Inflammation Type

	Immune dysregulation type		Inflammation type
	Systemic	Local	Th1	Th2
Allergic rhinitis	X			X
Asthma	X			X
Diabetes mellitus		X	X
Atopic dermatitis	X			X
Fibromyalgiaa	X		X
Inflammatory bowel disease	X		X
Osteoarthritis		X	X
Polycystic ovarian syndrome		X	X
Rheumatoid arthritis	X		X
Scleroderma	X		X
Sjogren's disease	X		X
Systemic lupus erythematosus	X		X
Uterine fibroids		X	X

^a The sensitivity analysis conducted moves fibromyalgia to the local immune dysregulation type.

Depression classification

Psychiatric history was assessed through telephone interviews using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID).⁴⁸ The SCID is recognized as the “gold standard” in diagnosing Major Axis I psychiatric disorders. All interviewers were trained to administer the SCID through in-person workshops that included video training procedures. Experts in the field of psychiatry led the training and held monthly assessment meetings to review and resolve any questionable diagnoses.

For the purposes of this analysis, women were characterized as having depression if they met DSM criteria for at least one of the following: dysthymic disorder, minor depressive disorder, major depressive disorder, having at least one major depressive episode (current or past), and/or depression not otherwise specified. Dysthymia was diagnosed according to DSM criteria as long as the participant met criteria for this disorder over a 2-year period. Age at first onset of each diagnosed mood disorder was assessed as well.

By utilizing the SCID, the age at first onset of depression was established. Along with the reported age at first onset of vulvar pain, we were able to determine the temporal association between psychiatric disorders and vulvodynia. Psychiatric morbidity was created by coding mood and anxiety disorders before age at first onset of vulvar pain in cases and reference age in controls. However, there is evidence to suggest a bidirectional relationship between depression and vulvodynia, where women with one of the two diseases are at higher risk for the other.⁹ Therefore, a combined outcome was used with the following categories: depression and vulvodynia, vulvodynia only, depression only, and neither.

Covariates

Based on literature, we a priori selected the following covariates as potential confounders between vulvodynia/depression and the type of inflammation and immune dysregulation: age, pack years of cigarette smoking (number of years smoked times the number of packs smoked per day), body mass index (BMI), and marital status.^49–52

Statistical analysis

Seven women were missing data on BMI (n = 5) or pack years (n = 2) and were excluded from the analysis. Multinomial logistic regression models were run to estimate the odds of being diagnosed with a specific condition (depression only, vulvodynia only, and both depression and vulvodynia) versus neither condition given the presence or absence of a specific type of inflammation. Given that there is a bidirectional association between vulvodynia and depression, those with neither condition were the reference group to avoid spuriously attenuating any associations seen.⁹

In separate regression models, four types of inflammation were examined: systemic immune dysregulation, local immune dysregulation, Th1 inflammation, and Th2 inflammation. In addition to crude models, an additional set of models adjusted for age, pack years, BMI, and marital status. In addition, a sensitivity analysis was conducted where fibromyalgia was categorized as local inflammation instead of systemic inflammation due to the inconclusive literature regarding fibromyalgia inflammatory processes.³⁹ All analyses were conducted using SAS v9.4 (SAS Institute, Cary, NC). Effect measure modification by race/ethnicity could not be assessed due to sparse data.

Results

Our analyses included 120 (26.8%) women with no diagnosis of vulvodynia or depression, 106 (23.7%) women with depression only, 97 (21.7%) women with vulvodynia only, and 124 (27.7%) women with both vulvodynia and depression (Table 2). Across these four groups, the majority of women identified as non-Hispanic white. BMI and pack years of smoking were similar across all four categories. Women with vulvodynia and depression were more likely to be single and there was no consistent trend with increasing education across the four groups. Women with vulvodynia and/or depression were more likely to experience one or more of the immune conditions as illustrated by the higher prevalence of immune dysregulation and inflammation type.

Table 2.

Participant Characteristics by Vulvodynia and Depression Status (N = 447)

	None (n = 120)	Depression only (n = 106)	Vulvodynia only (n = 97)	Vulvodynia and depression (n = 124)
Age (years)	31.1 (5.0)	31.7 (5.1)	28.7 (5.4)	29.1 (5.1)
BMI	25.8 (6.6)	27.8 (6.7)	25.0 (6.3)	26.1 (6.3)
Race
Non-Hispanic White	110 (91.7)	91 (85.9)	85 (87.6)	108 (87.1)
Nonwhite	10 (8.3)	15 (14.1)	12 (12.4)	16 (12.9)
Smoker
No	90 (75.0)	63 (59.4)	67 (69.1)	57 (46.0)
Yes	30 (25.0)	43 (40.6)	30 (30.9)	67 (54.0)
Mean pack years	3.3 (4.1)	5.2 (5.4)	3.9 (4.1)	5.1 (4.9)
Marital status
Single	27 (22.5)	27 (25.5)	28 (28.9)	40 (32.3)
Married/long-term partnership	93 (77.5)	73 (68.9)	69 (70.1)	76 (61.3)
Divorced/separated	0	6 (5.7)	1 (1.0)	8 (6.5)
Education
≤12 Years	1 (0.8)	6 (5.7)	3 (3.1)	8 (6.5)
High school/General Educational Development Test	17 (14.2)	13 (12.3)	17 (17.5)	27 (21.8)
Some college	12 (10.0)	14 (13.2)	8 (8.3)	17 (13.7)
2-Year college	59 (49.2)	38 (35.9)	50 (51.6)	49 (39.5)
4-Year college	31 (25.8)	35 (33.0)	19 (19.6)	23 (18.6)
Immune dysregulation
None	85 (70.8)	60 (56.6)	56 (57.7)	62 (50.0)
Systemic	10 (8.3)	14 (13.2)	15 (15.5)	37 (29.8)
Local	25 (20.8)	32 (30.1)	26 (26.8)	25 (20.2)
Inflammation type
None	85 (70.8)	60 (56.6)	56 (57.7)	62 (50.0)
Th1 only	21 (17.5)	23 (21.7)	18 (18.6)	31 (25.0)
Th2 only	14 (11.7)	23 (22.7)	23 (23.7)	31 (25.0)

Overall, women who had any immune dysregulation or inflammation had higher odds of either vulvodynia, depression, or both (Table 3). Women with systemic immune dysregulation were nearly five times more likely (adjusted odds ratio [aOR] = 4.93, confidence interval [95% CI]: 2.19–11.1) to report depression and vulvodynia. Women with systemic immune dysregulation were 1.61 (95% CI: 0.65–3.98) and 2.45 (95% CI: 1.00–5.96) times more likely to report depression and vulvodynia, respectively.

Table 3.

Odds of Vulvodynia/Depression by Immune Dysregulation and Inflammation Type

	Depression onlya		Vulvodynia onlya		Depression and vuvlodyniaa
	Crude estimate OR (95% CI)	Adjusted estimate aOR (95% CI)b	Crude estimate OR (95% CI)	Adjusted estimate aOR (95% CI)b	Crude estimate OR (95% CI)	Adjusted estimate aOR (95% CI)b
Immune dysregulation
Systemic	1.98 (0.83–4.76)	1.61 (0.65–3.98)	2.28 (0.96–5.43)	2.45 (1.00–5.96)	5.07 (2.35–10.97)	4.93 (2.19–11.10)
Local	1.81 (0.98–3.37)	1.89 (0.99–3.59)	1.58 (0.83–3.01)	2.12 (1.08–4.18)	1.37 (0.72–2.61)	1.96 (0.98–3.90)
None	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
Inflammation type
Th1	1.55 (0.79–3.06)	1.43 (0.70–2.92)	1.30 (0.64–2.66)	1.92 (0.90–4.10)	2.02 (1.06–3.85)	3.03 (1.48–6.19)
Th2	2.33 (1.11–4.89)	2.23 (1.05–4.77)	2.49 (1.18–5.25)	2.56 (1.20–5.49)	3.04 (1.49–6.18)	3.14 (1.49–6.60)
None	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.

^a Reference group for the outcome is those who have neither of the two conditions.

^b Adjusted by age, pack years, BMI, and marital status.

aOR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; OR, odds ratio.

Women reporting local immune dysregulation had similar odds of depression (aOR = 1.89, 95% CI: 0.99–3.59), vulvodynia (aOR = 2.12, 95% CI: 1.08–4.18), and comorbid depression and vulvodynia (aOR = 1.96, 95% CI: 0.98–3.90). Women with Th2 inflammation were 2.23 times more likely to have depression (95% CI: 1.05–4.77) and 2.56 times more likely to have vulvodynia (95% CI: 1.20–5.49) than women without Th2 inflammation. Women with Th2 inflammation had 3.14 times the odds of having both depression and vulvodynia (95% CI: 1.49–6.60).

Th1 inflammation was not as strongly associated with either depression (aOR = 1.43, 95% CI: 0.70–2.92) or vulvodynia (aOR = 1.92, 95% CI: 0.90–4.10) compared with the associations observed for Th2 inflammation. However, women with Th1 inflammation had a similar odds ratio for comorbid depression and vulvodynia (aOR = 3.03, 95% CI: 1.48–6.19) as that observed for Th2 inflammation.

In a sensitivity analysis, which categorized fibromyalgia as local immune dysregulation, no substantial differences in effect estimates were seen. We were unable to effectively assess study associations stratified by race/ethnicity due to the lack of heterogeneity in our study population.

Discussion

Although our confidence intervals were imprecise and some included the null value of 1, overall, our results suggest that women with immune dysregulation have higher odds of depression, vulvodynia, or both. In particular, systemic inflammation, rather than local inflammation, is more strongly associated with the presence of both vulvodynia and depression versus neither condition. Future studies utilizing a larger sample size will help improve the precision of these findings.

Our results are consistent with other findings that suggest that patients who have chronic inflammation, such as rheumatoid arthritis, are at increased risk of depression.^53–55 As noted earlier, this is thought to be driven by the imbalance in cytokines, namely an overdrive of Th1 activity in patients with autoimmune disease.^18,19 Women with vulvodynia are also more likely to present with conditions that cause chronic pain such as fibromyalgia and irritable bowel disease.⁵⁶

Much of the current literature for both depression and vulvodynia has focused on the role of Th1 rather than Th2 cytokines. Some have suggested a stronger association with Th1 cytokines, whereas others reported a stronger association with Th2 cytokines.^57–59 However, it is important to note that these studies have not looked at Th1 and Th2 within the same study population. Our findings suggest that an imbalance of either Th1 or Th2 immunity is associated with comorbid depression and vulvodynia.

However, within this population of women with a confirmed diagnosis of vulvodynia, Th2 imbalance may present a somewhat stronger association with risk of vulvodynia, depression, or both. This suggests that the reason some studies may have found stronger associations with Th1 and others with Th2 could be due to differences across study populations and/or because cytokines were not evaluated within the same participants.

Both types of immune dysregulation (systemic and localized) and inflammation type (Th1 and Th2) were associated with greater odds of having any of the comorbidities versus neither condition, with the highest odds for women with both comorbidities. This is in line with current literature that suggests that depression and vulvodynia share a potential pathophysiological profile.^9,10,60 Although few, if any, studies have looked at depression and vulvodynia together as an outcome; based on the literature for depression and vulvodynia individually, a potential biological rationale for the relationship between immune dysregulation/inflammation and comorbid vulvodynia and depression is through these cytokine pathways.

Current literature indicates that tumor necrosis factor-alpha, a Th1 cytokine, disrupts the tryptophan/serotonin pathway.⁶¹ This disruption leads to an activation of the Kynurenine pathway and causes dysregulation of the neuroendocrine stress axis, which is a potential underlying factor for depression.⁶¹ Although the mechanism for Th2 and depression is less clear, current evidence indicates there is an increased risk of depression in Th2-predominant disease states.^55,62,63 Overall, there is reason to believe that an imbalance of cytokines, regardless of T-helper cell origin, can result in an increased risk of depression.^21,59

This is likely a similar pathway for vulvodynia because there is emerging literature indicating that women who are diagnosed with vulvodynia have an increase in inflammatory markers and cytokines.^3,64 For example, women with a history of allergic reactions, recurrent yeast infections, or pain disorders are at higher risk for vulvodynia.^4,5,56 These exposures are often a consequence of immune dysregulation.

This analysis has both strengths and limitations. We have a relatively large sample of women with depression, vulvodynia, or both in this analysis and we were able to consider the effects of key covariates including pack years of cigarette smoking and BMI. However, this is a predominantly White non-Hispanic population, and we, therefore, were unable to examine differences by race/ethnicity. It is well documented that women of color may be underdiagnosed for both these conditions.^49,65,66 Therefore, it is possible our estimates are biased toward the null due to selection bias. In addition, there is the potential for misclassification of our immune dysregulation assignments because of the way in which disease states were categorized as Th1 versus Th2, and systemic versus localized inflammation.

Although some pathologies are clearly Th1 driven (e.g., rheumatoid arthritis) or Th2 driven (e.g., atopic dermatitis), other disease states are less well categorized and a category was assigned based on how the majority of studies have classified this condition.^19,33 Furthermore, a high versus low category was assigned to these different disease states based on what is known about the disease, but actual cytokine levels were never measured in these patients.

Immune health conditions were used as a proxy measure for immune dysregulation to then assess the association between immune dysregulation/inflammation and vulvodynia/depression. Future studies may benefit from measuring cytokine levels to improve categorization of the diseases as well as understanding of the mechanisms between immune dysregulation/inflammation and vulvodynia and/or depression.

Authors' Contributions

A.Z. contributed to methodology, software, formal analysis, and writing—original draft. J.G. was involved in conceptualization, methodology, and writing—review and editing. B.L.H. carried out conceptualization, methodology, and writing—review and editing.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health: NIH-NICHD0R01 HD058608.